This proposal details a comprehensive five-year mentored career development plan for the candidate, Dr. Joy Tsai, to transition to an independently-funded investigator in patient-based research with a focus on metabolic bone disease. Dr. Joy Tsai is an Instructor in Medicine at Harvard Medical School and Assistant in Medicine at Massachusetts General Hospital. She is well supported by the institution and will devote the majority of her time to clinical investigation. She will have full access to the rich resources of the Endocrine Unit, the Bone Density Center, Clinical Research Center, and Harvard Catalyst CTSC. She has chosen mentors with complementary expertise: Dr. Benjamin Leder is a leading clinical investigator in the field of bone and mineral metabolism. Dr. Mary Bouxsein is a leader in the field of biomechanics and cutting-edge imaging techniques. Both investigators have a strong record of mentorship with trainees progressing to academic independence. Both mentors are well-funded and are invested in this candidate's career development. The Scientific Advisory committee members (Dr. Henry Kronenberg, Dr. Joel Finkelstein, and Dr. Miriam Bredella) have expertise in skeletal physiology, clinical trials, and advanced musculoskeletal imaging and will provide scientific advice and career guidance during the transition to independent investigation. The research proposed in this grant aims to mechanistically define the effects of anabolic and antiresorptive therapy on bone quality. Current agents are unable to completely restore skeletal integrity in most patients with severe osteoporosis and are inadequate to match the anticipated rise in fracture incidence in our country's aging population. Thus, continued efforts to develop innovative evidence-based osteoporosis treatment strategies are crucial. This research plan proposes to utilize advanced high-resolution non-invasive imaging of bone and direct in vivo assessments of bone strength to assess changes in skeletal integrity. These techniques will allow for 1) the characterization of the changes in microarchitecture and estimated strength in women assigned a novel combination treatment strategy; 2) the characterization of the changes in bone material properties in women receiving the above combination therapy; and 3) the direct comparison of microarchitecture and estimated bone strength in women who have been previously exposed to bisphosphonates as compared with bisphosphonate-nave women. In so doing, this proposal will help define the effects of diverse therapies on bone quality, an understanding of which is crucial in the design of rational therapies for osteoporosis. The candidate's research activities will be complemented by structured career development activities. She will be trained in skeletal physiology concepts, principles of conduct of clinical research, biostatistics, and ethics of human research through formal coursework, national conferences, workshops, and daily interactions with her mentors and colleagues. In summary, this proposed K23 award will allow the candidate to gain the experience and training necessary to achieve her goal of becoming an independent clinical investigator.